Changes in the generation of reactive oxygen species and in mitochondrial membrane potential during apoptosis induced by the antidepressants imipramine, clomipramine, and citalopram and the effects on these changes by Bcl-2 and Bcl-X-L

In order to investigate the molecular mechanism of die antineoplastic effec ts exerted by the antidepressive agents imipramine, clomipramine, and cital opram, we examined the effects of these compounds on cell viability, genera tion of reactive oxygen species (ROS), and mitochondrial membrane potential (Delta Psi(m)) in human acute myeloid leukemia HL-60 cells. Our results in dicate that exposure to these compounds causes a loss in cell viability by activating the apoptotic process, as identified by electron microscopy, DNA gel electroprhoresis, and flow cytometry. The increased generation of ROS induced by these drugs was a relatively early event and preceded the loss o f Delta Psi(m). Overexpression of the aneiapoptotic protein Bcl-2 or Bcl-X- L prevents antidepressant-induced apoptosis, as well as loss of Delta Psi(m ), but does not affect the generation of ROS. (C) 1999 Elsevier Science Inc .